Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

EGG Consortium, Nicole M. Warrington, Robin N. Beaumont, Momoko Horikoshi, Felix R. Day, Øyvind Helgeland, Charles Laurin, Jonas Bacelis, Shouneng Peng, Ke Hao, Bjarke Feenstra, Andrew R. Wood, Anubha Mahajan, Jessica Tyrrell, Neil R. Robertson, N. William Rayner, Zhen Qiao, Gunn Helen Moen, Marc Vaudel, Carmen J. Marsit & 31 others Jia Chen, Michael Nodzenski, Theresia M. Schnurr, Mohammad H. Zafarmand, Jonathan P. Bradfield, Niels Grarup, Marjolein N. Kooijman, Ruifang Li-Gao, Frank Geller, Tarunveer S. Ahluwalia, Lavinia Paternoster, Rico Rueedi, Ville Huikari, Jouke Jan Hottenga, Leo Pekka Lyytikäinen, Alana Cavadino, Sarah Metrustry, Diana L. Cousminer, Ying Wu, Elisabeth Thiering, Carol A. Wang, Christian T. Have, Natalia Vilor-Tejedor, Peter K. Joshi, Jodie N. Painter, Ioanna Ntalla, Ronny Myhre, Niina Pitkänen, Elisabeth M. van Leeuwen, Raimo Joro, Elina Hypponen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.

LanguageEnglish
Pages804-814
Number of pages11
JournalNature Genetics
Volume51
Issue number5
DOIs
Publication statusPublished - 1 May 2019

ASJC Scopus subject areas

  • Genetics

Cite this

@article{4e88619976424d2591101fcb142e6fa4,
title = "Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors",
abstract = "Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.",
author = "{EGG Consortium} and Warrington, {Nicole M.} and Beaumont, {Robin N.} and Momoko Horikoshi and Day, {Felix R.} and {\O}yvind Helgeland and Charles Laurin and Jonas Bacelis and Shouneng Peng and Ke Hao and Bjarke Feenstra and Wood, {Andrew R.} and Anubha Mahajan and Jessica Tyrrell and Robertson, {Neil R.} and Rayner, {N. William} and Zhen Qiao and Moen, {Gunn Helen} and Marc Vaudel and Marsit, {Carmen J.} and Jia Chen and Michael Nodzenski and Schnurr, {Theresia M.} and Zafarmand, {Mohammad H.} and Bradfield, {Jonathan P.} and Niels Grarup and Kooijman, {Marjolein N.} and Ruifang Li-Gao and Frank Geller and Ahluwalia, {Tarunveer S.} and Lavinia Paternoster and Rico Rueedi and Ville Huikari and Hottenga, {Jouke Jan} and Lyytik{\"a}inen, {Leo Pekka} and Alana Cavadino and Sarah Metrustry and Cousminer, {Diana L.} and Ying Wu and Elisabeth Thiering and Wang, {Carol A.} and Have, {Christian T.} and Natalia Vilor-Tejedor and Joshi, {Peter K.} and Painter, {Jodie N.} and Ioanna Ntalla and Ronny Myhre and Niina Pitk{\"a}nen and {van Leeuwen}, {Elisabeth M.} and Raimo Joro and Elina Hypponen",
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Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. / EGG Consortium.

In: Nature Genetics, Vol. 51, No. 5, 01.05.2019, p. 804-814.

Research output: Contribution to journalArticle

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AU - Warrington, Nicole M.

AU - Beaumont, Robin N.

AU - Horikoshi, Momoko

AU - Day, Felix R.

AU - Helgeland, Øyvind

AU - Laurin, Charles

AU - Bacelis, Jonas

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AU - Hao, Ke

AU - Feenstra, Bjarke

AU - Wood, Andrew R.

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AU - Robertson, Neil R.

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AU - Qiao, Zhen

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AU - Vaudel, Marc

AU - Marsit, Carmen J.

AU - Chen, Jia

AU - Nodzenski, Michael

AU - Schnurr, Theresia M.

AU - Zafarmand, Mohammad H.

AU - Bradfield, Jonathan P.

AU - Grarup, Niels

AU - Kooijman, Marjolein N.

AU - Li-Gao, Ruifang

AU - Geller, Frank

AU - Ahluwalia, Tarunveer S.

AU - Paternoster, Lavinia

AU - Rueedi, Rico

AU - Huikari, Ville

AU - Hottenga, Jouke Jan

AU - Lyytikäinen, Leo Pekka

AU - Cavadino, Alana

AU - Metrustry, Sarah

AU - Cousminer, Diana L.

AU - Wu, Ying

AU - Thiering, Elisabeth

AU - Wang, Carol A.

AU - Have, Christian T.

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AU - Painter, Jodie N.

AU - Ntalla, Ioanna

AU - Myhre, Ronny

AU - Pitkänen, Niina

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